Phytochemicals and Phytoestrogens

“Phyto” means plant, so obviously phytochemicals means chemicals derived from a plant(s).  There are thousands of these chemicals and the real importance of only a few has been discovered.  The most talked about class of phytochemicals is called phytoestrogens.  Phytoestrogens are a diverse group of plant compounds that behave as estrogens and occur naturally in fruits and vegetables.  Their structural similarity to estrogens is probably the basis for their hormonal activity – they can bind at estrogen receptor sites inside the cells, causing estrogen-like effects.  Phytoestrogens have both a weak estrogenic and paradoxically, an anti-estrogenic activity.  This anti-estrogen activity results from competing for the positions at the estrogen receptor sites with the more powerful estrogens made by a woman’s own body – with the phytoestrogen attached to the site the more powerful estrogens are kept away.  Other activities of these plant chemicals include anti-cancer actions, blood vessel growth (angiogenesis) inhibition, and antioxidant properties.  Furthermore, the interactions of these pharmacologically active compounds are complex and are affected by digestion, metabolism, and absorption of the specific substances.  Keep in mind as you read this article; these are physiologically active substances, which have both positive and negative effects on the human body.

A Little History:

Plants were originally shown to have estrogenic activity in 1926.  One of the most dramatic examples of their effects was seen in the 1940s when sheep grazing on clover in Western Australia became infertile as a result of the plants’ powerful hormone activities.¹ By 1975, several hundred plants had been discovered that exhibited these kinds of activities.  Phytoestrogens were first found in the urine of humans in 1982. More than 1000 articles have been published in the past 30 years on phytoestrogens.

Three Main Classes of Phytoestrogens:

There are three main classes of phytoestrogens found in plants:

1)  Isoflavones.  Active isoflavones are found in a variety of plants including fruits and vegetables, but are predominantly found in legumes (beans, peas, and lentils), especially soybeans.   There are more than 1000 types of isoflavones, but the major ones are genistein and daidzein.  About 65% of the phytoestrogen in soy is in the form of daidzein.   Secondary soy products, such as soy flours and milks, contain lower amounts of isoflavones.²  For example, processed soy products, such as soy hot dogs and soy yogurt, contain only 1/10^th the isoflavone content of whole soybeans (0.2 to 0.3 mg vs. 2-4 mg of isoflavones /g).

2)  Lignans.   Estrogenically active lignans are called enterodiol and enterolactone.  Lignans are found widely in cereals, fruit and vegetables.  The highest concentration is in flaxseed (also known as linseed).

3)  Coumestans.    Coumestans occur predominately after germination; for example, in bean sprouts.

Vegetarians, such as the Seventh-Day Adventists, consume the most lignans and Asians, like people from Japan and Korea, consume the most isoflavones, largely in the form of tofu and miso.¹  The average Asian diet results in the ingestion of 20 to 150 mg of soy per day compared to 1 to 3 mg in the United States.³

Sex Hormone Effects:

Twelve ounces of soymilk drunk three times a day for one month will decrease a woman’s estradiol and progesterone levels, and her menstrual cycle length will be increased by about four days.⁴  Depressed hormone levels persist for 2 to 3 months after stopping the soy.  Japanese women are reported to have a very low incidence of hot flashes; possibly because of the soy isoflavones.  Hot flashes are reported by 70% to 80% of US menopausal women compared to 10 to 14% of women in Japan and Singapore.³ Postmenopausal American women who consume more soy products show estrogen effects on their vaginal tissues and a reduction in hot flashes.¹  The reduction in incidence of osteoporosis among soy consuming Asian women has been in part attributed to their intake of soy foods.

Cancer Effects:

Epidemiological studies of populations whose diets contain high levels of soy show that they have a much lower incidence of, and death from, hormone-dependent cancers, such as cancers of the breast and prostate.  A study from Singapore showed a decrease in breast cancer with increasing soy intake in premenopausal women (not postmenopausal).⁵  In laboratory studies, isoflavones can inhibit the growth of breast cancer and prostate cancer tissues.  However, in experimental animal studies that have shown cancer-inhibiting effects, the dosage of phytoestrogens used was huge and far greater than could be obtained in diet alone.³  Most important to keep in mind when considering the influence of soy is the bigger picture of the whole Asian diet: a diet low in fat and animal products, and high in grains and vegetables.

When consumed by young girls (before puberty) these phytoestrogens seem to cause the breast tissues to mature, thereby protecting the breast tissues from agents that cause cancer.¹  On the other hand, exposure of girls to soy’s phytoestrogens after puberty may cause an increase the risk of breast cancer.  This may be due to the direct effects of phytoestrogens on the breast tissues – similar to the way medically-prescribed estrogens increase a woman’s risk of cancer.  In June 2001, in the journal Cancer Research, investigators found genestein triggered reproductive abnormalities in aged mice, including adenocarcinoma, a rare form of cancer.⁶  If these cancer-promoting effects are found to be valid in humans, then the present day encouragement for Western women, who are at the greatest risk of breast cancer, to increase their phytoestrogen intake would not be wise.

Heart Disease Effects:

Non-hormonal benefits are also found with the consumption of soy products.  People living in countries, for example, Japan, with more soy in their diet, have a lower risk of heart attacks.   One reason for this may be that soy-feeding causes a decrease in total and “bad” LDL cholesterol, and an increase in “good” HDL-cholesterol.   Soy foods may also prevent heart attacks by inhibiting the tendency to form blood clots (thrombosis) in the blood vessels supplying the heart muscle, by their antioxidant activities, and by making the blood vessels’ muscular walls more compliant. Most likely, rather than the isoflavones, other components of the soybean account for these heart disease reducing effects; because the beneficial effects of soy are seen with products that are low, as well as high, in isoflavones.⁷  Again, consider the bigger picture of the impact of the starch-based (rice), low meat, high vegetable Asian diet.  Don’t be misled into believing that heart disease prevention is accomplished by sprinkling “soy bacon bits” on your eggs in the morning.

Thyroid Effects:

Goiter and hypothyroidism have been reported in infants receiving soy formula.  Autoimmune diseases of the thyroid and thyroid cancer may also be caused by exposure to antithyroid flavonoids in soy.⁸

My Greatest Concern: Bottle-Fed Infants

Sex Hormone Effects:

Soy protein is one of the cheapest sources of protein and has been used as a substitute for breast milk since the turn of the 20^th century.  Soy-based formula is used by 25% of infants in the US or about 750,000 infants per year.  In the US soy formula is available over-the-counter, where as in Europe, it is by doctor’s prescription only.  Soy formula exposes infants to high levels of the estrogen isoflavones, genistein and daidzein.  On average, infants on soy formula have 10 times greater levels of isoflavone exposure than Japanese who consume soy (11 mg/day vs. 1 mg/day) and 200 times greater than infants fed cow-milk or breast milk.⁹  Total plasma levels of isoflavones are 22,000 times greater than estradiol levels in the infants.  Fortunately, the estrogenic activity is 1/1,000^th to 1/10,000^th less than estradiol – the natural powerful estrogen found in people’s bodies.  When adjusted for body weight, these studies show that infants exclusively fed soy-based formulas are exposed to a daily dose of isoflavones that is four- to 13-fold higher than the 0.7 mg/kg intake that has been shown to exert significant physiologic effects on the hormone regulation of a women’s menstrual cycle.¹⁰

Exposing the developing tissues of the infant to these dosages of unnatural hormones is of great concern to researchers.  Most concerning is that, these hormones may affect the developing brain and reproductive tissues.  Possible consequences of this hormone activity may have already been seen.  There is an increased incidence of hypospadia in male offspring of vegetarian mothers consuming soy products.¹¹  Hypospadia is a birth defect where the urethra opens at the base of the penis rather than the tip. On the other hand, the adverse effects of soy formula may not be apparent until later in life. For example, women fed soy formula as infants had a small average increase in duration of their menstrual cycle and greater discomfort with menstruation. ¹²  Also, a 4-fold increase in multiple births was seen in women who had received formula.^12-13

Immune System Effects:

Phytoestrogens may also exert their effect on the immune system.  Consider these observations:

• In experimental studies, genistein produced suppression of the immune system of mice fed doses comparable to those fed infants on soy formula.¹⁴  The size of the thymus gland was reduced after soy feeding.

• Women fed soy-formula as infants were found to have almost a 90% increase in regular use of asthma and allergy drugs.¹² 

• There are reports that the immune proteins (gamma globulins and immunoglobulins) and antibodies to vaccinations are decreased in soy-fed infants.^15-16 

• Respiratory infections and bronchitis were found to be increased in soy-fed infants.^15,17

• Children with autoimmune diseases were more likely to have received soy-formula as infants.¹⁸

• Women taking a synthetic isoflavone derivative to prevent osteoporosis were found to have a depressed white blood count.¹⁹

Adults taking soy “health-food” supplements can ingest levels several times higher than would be expected from a diet containing soy and may place them at risks similar to infants consuming soy formula.

McDougall’s Recommendations:

Despite concerns, there is no definite evidence that soy is harmful at levels normally consumed.   Consider the tens of millions of people living in Japan, consuming soy products throughout their life, and they enjoy the longest life expectancy of the people of any country (Japanese women are expected to live 84.93 years, compared to US women of 79.5 and Japanese men to 78.07 years, compared to 74.1 for US men).

I believe that use in amounts similar to those seen in Asian populations is without harmful effects, and is actually beneficial.  Therefore, we have always recommended, and will continue to recommend, that people use soy products as condiments in their meals; such as small pieces of tofu cut up in a rice “stir-fry,” soy milk on their cereal or in cooking, or an occasional soy hot dog.

I do have serious concern for people consuming very high amounts of soy protein in the form of “fake meats,” like soy burgers and luncheon meats.  The first ingredient listed is isolated soy protein – as much as 70% of the calories comes from this ingredient.   Many people looking for better health through a shift towards a more vegetarian diet are switching to these familiar looking and tasting products.  I believe this is an unhealthful move and will result in, at the very least, a diet too high in protein, and too low in dietary fiber and other beneficial substances found in wholesome fruits and vegetables.  Another potential source of problems is supplements, intended as pills, to treat menopausal-related problems, like hot flashes and osteoporosis.  We simply don’t know the effects of all this concentrated soy protein found in “fake meats” and supplements, consumed over long periods of time.  Even if the adverse outcomes are relatively uncommon, the potential for a major public health impact is large.

The popular press and the buying public focus on soy products and flaxseed as if they were the only source of phytochemicals.  The truth is that all plant foods are teeming with these compounds.  A few have been found and many hundreds more are still to be discovered.  For now, every time you eat plant foods think, “I am bathing the inside of every cell in my body with an abundant supply of miraculous substances that will ultimately make every part of me radiate with good health.”   The most prudent action for you to take is to eat a variety of plant foods – starches, vegetables and fruits – all properly designed for your health and youthful appearance through millions of years of evolution.

References:

1)  Murkies A.  Clinical review 92: Phytoestrogens.  J Clin Endocrinol Metab. 1998 Feb;83(2):297-303.

2)  Tham D.  Clinical review 97: Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab. 1998 Jul;83(7):2223-35.

3)  Glazier M.  A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy.  Arch Intern Med. 2001 May 14;161(9):1161-72.

4) Lu L. Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction.
Cancer Epidemiol Biomarkers Prev. 1996 Jan;5(1):63-70.

5)  Lee H. Risk factors for breast cancer by age and menopausal status: a case-control study in Singapore. Cancer Causes Control. 1992 Jul;3(4):313-22.

6)  Newbold R.  Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res. 2001 Jun 1;61(11):4325-8.

7)  Jenkins D.  Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women.  Am J Clin Nutr. 2002 Aug;76(2):365-72.

8)  Divi R.  Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action.  Biochem Pharmacol. 1997 Nov 15;54(10):1087-96.

9)  Setchell  K.  Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997 Jul 5;350(9070):23-7.

10)  Cassidy A.  Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.  Am J Clin Nutr. 1994 Sep;60(3):333-40.

11)  North K.  A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.  BJU Int. 2000 Jan;85(1):107-13.

12 Strom B.  Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood.  JAMA. 2001 Aug 15;286(7):807-14.

13)  Goldman L.  Exposure to soy-based formula in infancy.  JAMA. 2001 Nov 21;286(19):2402-3.

14)  Yellayi S.  The phytoestrogen genistein induces thymic and immune changes: a human health concern?  Proc Natl Acad Sci U S A. 2002 May 28;99(11):7616-21.

15)  Zoppi G.  Immunocompetence and dietary protein intake in early infancy. J Pediatr Gastroenterol Nutr. 1982;1(2):175-82.

16)  Zoppi G.  Gammaglobulin level and soy-protein intake in early infancy.  Eur J Pediatr. 1979 Apr 25;131(1):61-9.

17)  Zoppi G.  Diet and antibody response to vaccinations in healthy infants. Lancet. 1983 Jul 2;2(8340):11-4.

18)  Fort P. and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children. J Am Coll Nutr. 1990 Apr;9(2):164-7.

19)  Alexandersen P.  Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial.  JAMA. 2001 Mar 21;285(11):1482-8.

©2002 John McDougall All Rights Reserved